JPH0237344B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel oxyacetic acid derivatives. Conventional blood lipid-lowering agents include bezaifbrate, clofibrate, related drugs, nicotinic acid derivatives, hormone preparations such as anabolic steroids, unsaturated fatty acids such as linoleic acid, cholestyramine, and β-sitosterol. It is used. The present inventors synthesized a series of oxyacetic acid derivatives and examined various effects on living organisms, and as a result, the general formula (In the formula, R ¹ is a hydrogen atom, a naphthoyl group, a cyclohexylcarbonyl group, a pyridicarbonyl group, a furoyl group, a thenoyl group, a 3,4-methylenedioxybenzoyl group, an alkanoyl group having 2 to 18 carbon atoms,
Oxyacetic acid derivatives represented by a chlorobenzenesulfonyl group or an α-(chlorobenzoyl)-phenoxy-α-cyclohexylacetyl group ( ^R2 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms) are excellent in lowering blood lipids. It has been found that it has an effect. In the compound of the formula, examples of the alkanoyl group for R ¹ include a butyryl group and a palmitoyl group. The oxyacetic acid derivative of formula () has the general formula (In the formula, R ³ is a group R ¹ −NH− or

A ^hydroxy compound represented by the general formula It can be produced by reacting with α-halogeno-cyclohexyl acetic acid ethyl ester represented by the formula (wherein X is a halogen atom and R ⁴ is a lower alkyl group having 1 to 4 carbon atoms) and hydrolyzing if necessary. As X in the compound, an iodine atom, a bromine atom or a chlorine atom is preferable. This reaction is usually carried out using an equimolar amount of α-halogenocyclohexyl acetate () relative to compound (), and one may be used in excess. This reaction is preferably carried out in the presence of a solvent.
As the solvent, any organic solvent that is inert under the reaction conditions can be used, for example dimethylformamide or acetone, and the reaction may be carried out in a mixed solvent. The reaction can also be promoted by adding a base such as potassium carbonate, sodium carbonate, sodium methylate, sodium ethylate. The reaction product of the base and the compound () may be removed from the reaction system and then reacted with the compound (). Reaction conditions such as temperature, time, pressure, etc. are appropriately determined depending on the raw materials, solvent, base, etc. used. This reaction usually takes about 2 to 4 days at room temperature.
When heated to 100 to 180°C, the process is completed in 5 to 20 hours. The compound thus obtained can be hydrolyzed in the presence of an acid or an alkali, if necessary.
For example, by heating in a mineral acid aqueous solution such as a hydrochloric acid aqueous solution or a sulfuric acid aqueous solution for 1 to 5 hours, a compound of formula () in which R ¹ and R ² are hydrogen atoms is obtained. Further, when hydrolyzed using an aqueous solution such as sodium hydroxide or potassium hydroxide, a compound of formula () in which R ² is a hydrogen atom is obtained. The reaction product () is isolated and purified by known separation means, such as concentration, vacuum concentration, distillation, vacuum distillation, fractional distillation, liquid conversion, solvent extraction, crystallization, recrystallization, dissolution, chromatography, etc. can do. The novel oxyacetic acid derivative () exhibits a remarkable blood lipid-lowering effect and is useful, for example, as a blood lipid-lowering agent for the treatment of hyperlipidemia. This compound () has low toxicity and is effective against clofiplate [ethyl-α-(p-chlorophenoxy)-isobutyrate], bezafibrate [2-{4-[2-4-chlorobenzamide)-ethyl]-phenoxy}- 2
It is also superior in that it does not cause liver damage as seen with methylpropionic acid and the like. The blood lipid-lowering agent containing the new compound as an active ingredient can be prepared into tablets, capsules, powders, etc. by conventional formulation techniques.
In addition to being used orally as granules, it can also be administered parenterally as injections, suppositories, pellets, etc. Furthermore, this drug can be used in combination with other drugs, such as other hyperlipidemia therapeutics, antihypertensive agents, thrombosis-inhibiting agents, etc. Dosage varies depending on the compound, but is usually between 25 and 25 doses per adult per day.
Oral administration of 2500 mg, preferably 100-1000 mg can achieve the objective. The compounds of formula also have antithrombotic and anti-inflammatory effects. Example 1 690 mg (0.03 mg) of sodium in 60 ml of absolute ethanol
8.52 g (0.03 mol) of 4-(1-naphthoylaminoethyl)-phenol was added,
Stir for 30 minutes at room temperature. After ethanol was distilled off under reduced pressure, the residue was dissolved in 60 ml of dimethylformamide, 8.10 g (0.033 mol) of α-bromocyclohexyl acetic acid ethyl ester was added, and the mixture was boiled and refluxed for 8 hours. Next, dimethylformamide was distilled off under reduced pressure, and the residue was dissolved in 200 ml of benzene and diluted with water, 10%
After sequentially washing with NaOH aqueous solution and water, the benzene layer is dried with anhydrous sodium sulfate. When the benzene was distilled off under reduced pressure and the residue was recrystallized from ethanol-n-hexane, 7.3 g of α-[4-(1-naphthoylaminoethyl)-phenoxy]-α-cyclohexyl acetic acid ethyl ester of the following formula ( Yield: 53.8%).
Melting point 99.5-100.5℃. Example 2 Potassium hydroxide 790mg in 30ml ethanol
(0.0142 mol) was dissolved, and α-[4-(1-
naphthoylaminoethyl)-phenoxy]-α-cyclohexyl acetic acid ethyl ester 3.0 g (0.0071
mol) and react at 50-60°C for 2 hours. After the reaction is complete, ethanol is distilled off under reduced pressure and the residue is dissolved in water.
Dissolve in 100 ml, add 10% hydrochloric acid, collect the precipitate, wash thoroughly with water, and recrystallize from ethanol-water to obtain α-[4-(1-naphthoylaminoethyl)-phenoxy]- 2.8 g (93.3%) of α-cyclohexyl acetic acid is obtained. Melting point 114~
115.5℃. Example 3 Sodium 690 mg (0.03
6.75 g (0.03 mol) of 4-(N-benzylideneiminoethyl)phenol was added thereto, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and 60 ml of dimethylformamide was added to the residue.
-Bromo-cyclohexyl acetic acid ethyl ester
Add 7.47 g (0.03 mol), boil and reflux, and react for 8 hours. The solvent is then distilled off under reduced pressure, and the residue is dissolved in water and extracted with benzene. After washing the benzene layer with 10% NaOH aqueous solution and water and drying with anhydrous sodium sulfate, benzene was distilled off under reduced pressure.
9.8 g of -[4-(N-benzylideniminoethyl)-phenoxy]-α-cyclohexyl acetic acid ethyl ester are obtained. 9.0 g (0.023 mol) of this compound was dissolved in 72 ml of 10% hydrochloric acid, boiled and refluxed for 3 hours, 300 ml of water was added to the residue, washed three times with benzene, and the water was distilled off under reduced pressure to dryness. When this is recrystallized from ethanol-ether, α-
3.9 g (yield 54.1%) of [4-(aminoethyl)-phenoxy]-α-cyclohexyl acetic acid hydrochloride is obtained. Melting point 220-225℃. Similarly, the following compounds are obtained.

【table】

[Table] Formulation Example 1 400 g of α-[4-(1-naphthoylaminoethyl)-phenoxy]-α-cyclohexyl acetic acid ethyl ester, 400 g of finely powdered silicon dioxide, and 185 g of corn starch were uniformly mixed and then kneaded. Place in a machine, add 1000 ml of 3% hydroxypropylcellulose aqueous solution, and knead. The mixture is sieved and granulated using a 16-mesh sieve, and dried with air at 50°C. The mixture is then sieved through a 16-mesh sieve to form granules of a blood lipid-lowering agent. Formulation example 2 α-[4-(1-naphthoylamino-ethyl)-
400 g of [phenoxy]-α-cyclohexyl acetic acid, 400 g of lactose and 175 g of potato starch are mixed uniformly and placed in a kneading machine, and 400 ml of a 3% hydroxypropylcellulose aqueous solution is added thereto and kneaded.
The mixture is sieved through a 16-mesh sieve, and the granules are mixed with 0.3% magnesium stearate and compressed into tablets of a blood lipid-lowering agent. Test Example 1 Antilipidemic effect in dietary hyperlipidemic rats: Wistar male rats (body weight approximately 140 g)
A group of 6 animals was used. Cholesterol in animals2
%, sodium cholate 1%, and coconut oil 5% were fed for 4 days to induce hyperlipidemia. The test substance was suspended in 0.5% Tween-80 and orally administered at a dose of 100 mg/Kg once a day for 4 days at the same time as the start of feeding. 24 from last dose
Blood was collected after a period of time, and the total cholesterol concentration in plasma was determined by the Turkowski method [Clinical Chemistry, Vol. Vol. 10, p. 451 (1964)]. The liver weight was determined by removing the liver, weighing it, and expressing it as a weight ratio to body weight. For comparison, black fibrate and bezafibrate were used. These have the structural formula below. The test results are shown in Table 2.

【table】

[Table] Test Example 2 Acute Toxicity: Ten male mice weighing 22 to 25 g were used as one group, and the test substance was dissolved in olive oil and administered orally in an amount corresponding to the body weight. LD ₅₀ was calculated from the mortality rate after 72 hours by the area method. As a result, the LD ₅₀ of compounds 9, 10, 11 and 13 of the present invention was all 4000 mg/Kg.
It was hot.

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is a hydrogen atom, a naphthoyl group, a cyclohexylcarbonyl group, a pyridylcarbonyl group, a furoyl group, a thenoyl group, a 3,4-methylenedioxybenzoyl group, an alkanoyl group having 2 to 18 carbon atoms, a chlorobenzenesulfonyl group, or α -(chlorobenzoyl)-phenoxy-α-cyclohexylacetyl group, R ² is a hydrogen atom or has 1 to 4 carbon atoms
oxyacetic acid derivative represented by (representing a lower alkyl group).